Radiohalogenated benzazepine derivatives and method of imaging dopamine receptors therewith

ABSTRACT

Novel CNS dopamine D-1 receptors, such as the compound (±)-8-chloro-2,3,4,5-tetrahydro-3-methyl-5-(4&#39;-[ 125  I]iodophenyl)-1H-3-benzazepine-7-ol, are disclosed. These compounds are useful as imaging agents for D-1 receptors in the human brain and exhibit good brain retention and in vivo stability.

This is a division of application Ser. No. 332,625, filed Apr. 3, 1989,now U.S. Pat. No. 5,068,326.

BACKGROUND OF THE INVENTION

This invention relates to benzazepine derivatives which are selectivefor dopamine D-1 receptors, to methods of preparing such compounds, tomethods of utilizing them as imaging agents, and to novel compoundsuseful as intermediates in the preparation of such D-1 receptors.

For the treatment of a wide variety of different nervous and mentaldiseases, it is desirable to be able to monitor the effectiveness ofdrugs and substances which affect brain chemistry. For instance, in thetreatment of schizophrenia or Parkinson's Disease, it is highlydesirable to be able to gauge the biochemical effects of drugsadministered for blocking the patient's dopamine receptors. If toolittle of the drug is administered, the desired blockade does not occur,and if too much of the drug is administered, there can be severe sideeffects.

New and powerful imaging methods which enable one to assess the livingbrain in vivo and thereby monitor the effectiveness of drugs andsubstances that affect brain chemistry have recently been developed.Methods such as positron emission tomography (PET) and single photonemission tomography (SPECT) involve the administration to a patient ofradioactive tracer substances comprising a ligand that binds topresynaptic or postsynaptic neuroreceptors in the patient's brain.Emissions (primarily gamma rays which are emitted from the positrons orphotons emitted from the radioactive tracer) are measured. Theseemissions are indicative of the number and degree of occupancy ofblocking of the neuroreceptors. The number of neuroreceptors and thedegree of occupancy or blocking is calculated utilizing a mathematicalmodel, and compared with an intra-person or inter-person control, todetermine the degree of drug response. Further treatment of the patientwith drugs is based upon the comparisons made.

It is generally accepted that there are two subtypes of dopaminereceptors, designated as D-1 and D-2 receptors. Recent reports havesuggested that these two subtypes of receptors exhibit oppositebiochemical effects: D-1 agonists stimulate adenyl cyclase activity,while D-2 agonists inhibit the enzyme activity. It is clear that thesereceptor subtypes influence each other, and yet they display separateand distinct functions on body physiology and biochemistry. Monitoringof D-1 receptors in a patient is important for assessing thedopaminergic system and ultimately assisting patient management.

The compoundR-(+)-8-chloro-2,3,4,5-tetrahydro-3-methyl5-phenyl-1H-3-benzazepine-7-ol(SCH-23390) is a highly selective central D-1 antagonist. O'Boyle, K.M., Waddington, T. L., Eur. J. Pharmacol., 1985, 115, 291; Seeman, P.,Niznik, H. B., Atlas of Science: Pharmacology 161, 1988. Thecorresponding bromo- and iodo- compounds (SKF-83566 and IBZP,respectively) have also been shown to have a high specificity forcentral D-1 dopamine receptors. Friedman, A. M., Dejesus, O. T.,Woolverton, W. L., et al., Eur. J. Pharmacol., 1985, 108, 327; Manik, C.P., Molinoff, P. B., McGonigle, P., J. Neurochemistry, Vol. 51, No. 2,p. 391, 1988; Kung, H. F., Billings, J., Guo, Y.-Z., Blau, M.,Ackerhalt, R. A., Intl. J. Nucl. Med. Biol., 1988, 15, 187; McQuade, R.D., Chipkin, R., Amlaiky, N. et al., Life Sciences, Vol. 43, pp.1151-1160 (1988). The in vitro affinity constants for these compounds inthe rat striatum tissue preparation are set forth in Table 1.

                  TABLE 1                                                         ______________________________________                                        Chemical Structures and In Vitro Binding Constants                            of Benzazepines                                                                ##STR1##                                                                     Compound         X     Kd(nM)                                                 ______________________________________                                        SKF-83692        H     197                                                    SCH-23390        Cl    0.36                                                   SKF-83566        Br    2.32                                                   IBZP             I     0.7                                                    ______________________________________                                    

The bromo compound SKF-83566 labeled with ⁸⁶ Br, a positron emittingradionuclide, has been used for PET (positron emission tomography)imaging in a rhesus monkey, which showed the highest concentration inthe basal ganglia, with more selectivity in the posterior aspect of thecaudate nucleus, the region with high D-1 receptor density. Friedman, A.M., Dejesus, O. T., Woolverton, W. L., supra. Several recent reportshave indicated that in conjunction with PET, [¹¹ C]SCH-23390 showed thehighest concentration in the basal ganglia area of the human brain.Farde, L., Halldin, C., Stone-Elander, S., et al., Psychopharmacol.,1987, 92, 278; McQuade, R. D., Ford, D., Duffy, R. A., Chipkin, R. D.,Iorio, L. C. and Barnett, A., Life Sciences, Vol. 43, pp. 1861-1869(1988).

The potential of a radioiodinated benzazepine derivative, [¹²⁵ I]BZP asa specific CNS D-1 dopamine receptor imaging agent for SPECT has beenreported. Kung, H. F., Billings, J., Guo, Y.-Z., Blau, M., Ackerhalt, R.A., Id. The agent exhibited good localization in rat brains after anintravenous injection, with an uptake of 2.7, 1.2, 0.8 and 0.26%dose/organ at 2, 15, 30 and 60 minutes post injection, respectively.The regional distribution of [¹²⁵ I]BZP in rat brain, as measured by invivo autoradiography, displayed a high uptake in the caudate putamen,accumbens nucleus and substantia nigra, regions known to have a highconcentration of D-1 dopamine receptors. The uptake ratio ofstriatum/cerebellum increased with time. At thirty seconds and two hoursafter injection, the ratios were 1.1 and 5.3, respectively. The specificuptake regions (as measured by in vivo autoradiography), rich in D-1dopamine receptors, can be blocked by pretreatment with SCH-23390, aselective D-1 dopamine receptor antagonist.

IBZP suffers two major disadvantages as a potential imaging agent. Thefirst disadvantage is the poor in vivo and in vitro stability of thecompound based on observations of the in vivo biodistribution study of[¹²⁵ I] IBZP in rats. The thyroid uptake is high at later time points,which strongly suggests the availability of free iodide in the bloodcirculation due to in vivo deiodination. Deiodination may take placebecause the radioactive iodine is at an activated position, ortho to thehydroxyl group on the benzene ring. The second drawback of [¹²⁵ I]IBZPis its short retention time in the brain. In a normal SPECT study of thebrain, it takes about thirty to sixty minutes for the data acquisition.It is necessary to use an agent exhibiting a prolonged retention time inthe target region (in this case, basal ganglia) for SPECT imagingstudies.

Although the compound SCH-23390 is a highly selective D-1 antagonist,its use as an imaging agent is diminished by the absence of adiagnostically suitable radioisotope such as ¹²³ I.

There is, therefore, a need for improved CNS D-1 dopamine receptorimaging agents which overcome the disadvantages of the various imagingagents known in the art.

SUMMARY OF THE INVENTION

Test results indicate that the novel compounds of Formula I are highlyselective for the CNS D-1 receptor and should therefore possess utilityas imaging agents for evaluation of such receptors. ##STR2## where X=OH,Cl or CH₃ ;

Y=H, Cl, or CH₃, provided that, when X=Cl, then Y=H or CH₃ and when Y=Hor CH₃, then X=Cl;

Z=Hal (halogen); C=CH-Hal; C₁ -C₁₀ alkylene-Hal; C₁ -C₁₀alkylene-C=CH-Hal; C₁ -C₁₀ alkylene-phenyl-Hal; or C₁ C10alkylene-heteroaryl-Hal; and

A=H, C₁ -C₅ alkyl, C₁ -C₅ alkylene-phenyl; or C₁ -C₅alkylene-heteroaryl.

This invention therefore relates to the novel compounds of Formula I, tomethods of preparing them and to methods of utilizing them as imagingagents for the evaluation of CNS D-1 receptors. This invention furtherrelates to novel compounds of Formula II which are useful asintermediates for preparing the novel compounds of Formula I. ##STR3##where Q=Hal, SnBu₃, Si(R)₃ or HgR; X, Y and A are as defined above, and

R=C₁ -C₅ alkyl.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a bar graph showing ratios (based on % dose/gram) of regionalcerebral uptake of [¹²⁵ I]FISCH (CX: cortex, ST: striatum, CB:cerebellum). Only ST/CB ratio shows the dramatic increase with time,suggesting that the agent is concentrated in the target tissue, in whichthe concentration of D-1 dopamine receptors is high.

FIG. 2 is a graph showing the saturation binding curve of [¹²⁵ I]FISCHin rat striatum. The radiolabeled [¹²⁵ I]FISCH binds to rat striatalhomogenate with high affinity. The saturation curve indicates that thisligand demonstrates a low nonspecific binding (approximately 15% at Kd).

DETAILED DESCRIPTION OF THE INVENTION

Compounds of this invention may be made by methods analogous to thatillustrated in Scheme A for the preferred compound of this invention,(±)-8-chloro-2,3,4,5-tetrahydro-3-methyl-5-(4'-[¹²⁵ I]iodophenyl)-1H-3-benzazepine-7-ol, referred to hereinafter as FISCH.

SCHEME A ##STR4##

As shown in Scheme A, the 4'bromo-benzazepine, 3, may be prepared from3-chloro-4-methoxyphenethyl amine, 1, using methods disclosed by Wyrick,S. C., Mailman, R. B., J. Label. Compd. and Radiopharm., 1984, 22, 189,the disclosure of which is hereby incorporated by reference. The4'bromo-benzazepine, 4, may be prepared by N-methylation of 3 withformaldehyde and formic acid. Lithiation of 4 with n-butyllithium at -78C., to replace the 4'-bromo group, followed by the addition oftri-n-butyltin chloride, affords the desired tri-n-butyltin derivative,5. The final product, 7, may be prepared by contacting 5 with iodine(I₂) and then deprotecting the hydroxy group with a suitabledeprotecting agent such as boron tribromide or a strong acid to give thefinal product, 7, FISCH. Although Scheme A illustrates the use of thetributyltin intermediate 5, other intermediates within the scope ofFormula II could also be utilized.

Radiolabeled compounds of the invention ma be prepared by methodsanalogous to those illustrated in Scheme B for radiolabelling of FISCH.

SCHEME B ##STR5##

Intermediate compound 5 is labeled with, for example, I-125 atcarrier-free level by an electrophilic radioiodination reaction using anoxidant such as hydrogen peroxide. The radiolabeled compound, 6, isseparated from the starting material, 5 , by HPLC. The carrier-free [¹²⁵I] 6 is O-demethylated by boron tribromide and the desired final product[¹²⁵ I]FISCH, 7, is separated again from the impurity by HPLC. Although¹²⁵ I-isotopes are useful for laboratory testing, they will generallynot be useful for actual diagnostic purposes because of the relativelylong half-life (60 days) and low gamma-emission (30-65 Kev) of ¹²⁵ I.The isotope ¹²³ I has a half life of 13 hours, gamma energy 159 keV),and it is therefore expected that labeling of ligands to be used fordiagnostic purposes would be with this isotope. Other isotopes which maybe used include ¹²¹ I (half life of 2 hours).

Evaluations of FISCH indicate that it shows good brain uptake in rats.The high initial uptake (2.27% dose/organ) at two minutes afterinjection indicates that the compound passes through the blood-brainbarrier with ease.

The maximum brain uptake for rats, i.e. 100% first pass extraction, isbetween 2.5-4.0% of the injected dose. Kung, H. F. in Fritzberg, A.,ed., Advances in Radiopharmaceuticals, CRC Press, Boca Raton, Fla.,1986, Vol. 1, pp. 21-40. At later time points, brain uptake decreases;at one hour after injection of all of the [¹²⁵ I]FISCH, activity hadwashed out from the brain (0.55% dose/organ). The brain retention at onehour post injection was much better than that of [125I]IBZP (0.26%dose/organ).

High initial uptake of FISCH in the lungs was also observed with rapidclearance at fifteen and sixty minutes. Liver uptake remains highthroughout the first hour. The relatively low thyroid uptake at one hourpost injection (0.04%) suggests that little in vivo deiodination of [¹²⁵I]FISCH has occurred. As compared with [¹²⁵ I]IBZP, which showed athyroid uptake of 0.1% at one hour post injection, the new iodinated D-1agent of this invention, [¹²⁵ I]FISCH, containing an iodine atom at the4'-position, displays better in vivo stability.

Utilizing a brain regional dissection technique, the stratum/cerebellum(ST/CB) ratio (target to nontarget ratio) for FISCH displayed a dramaticincrease with time: 1.24, 1.80 and 2.47 at two, fifteen and sixtyminutes, respectively. These data are consistent with the distributionpattern obtained with in vivo autoradiography.

Tests to determine in vitro bonding of [¹²⁵ I]FISCH and [¹²⁵ I]TISCH(the 3'-iodo analog of FISCH) indicate that the compounds bind with highaffinity to rat striatal homogenate. The saturation curve shown in FIG.2 indicates that this ligand has a fairly low nonspecific binding(approximately 15% at Kd). The specific binding of [¹²⁵ I]FISCH and [¹²⁵I]TISCH (racemic mixture) was found to be saturable and displayed a Kdof 1.43 and 0.35 nM, respectively. These values were comparable to thosefor [¹²⁵ I]IBZP (R-(+), active form), measured under similar conditions.Competition data of various compounds for [11²⁵ I]FISCH and TISCHbinding are presented in Tables 2 and 3. The results indicate that [¹²⁵I]FISCH and TISCH bind specifically to the dopamine D-1 receptor withhigh selectivity.

                  TABLE 2                                                         ______________________________________                                        Inhibition Constants of Compounds on                                          [.sup.125 I]FISCH Binding to Rat Striatal Membranes*                           ##STR6##                                                                     Compound       ki (nM, mean + SEM)                                            ______________________________________                                        (±) FISCH   1.71 ± 0.17                                                 SCH-23390      0.39 ± 0.04                                                 (±) IBZP    13.40 ± 0.54                                                (-) -Apomorphine                                                                             888 ± 115                                                   WB 4101**      1270 ± 203                                                  ketanserin     >3000                                                          spiperone      >3000                                                          ______________________________________                                         *0.15-0.30 nM [.sup.125 I]FISCH was incubated in the presence of the          indicated compounds in 7-11 concentrations and of membrane preparation        from rat striatum. Each value represenets the mean ± SEM of three to       five determinations.                                                          **WB4101 is the compound                                                      2(2,6-dimethoxyphenoxyethyl)-aminomethyl-1,4-benzodioxane hydrochloride  

                  TABLE 3                                                         ______________________________________                                        Inhibition Constants of Compounds on                                          [.sup.125 I]TISCH Binding to Rat Striatal Membranes*                          Compound      ki (nM, mean + SEM)                                             ______________________________________                                        (R)-SCH-23390 0.41 ± 0.04                                                  (±)-TlSCH  0.55 ± 0.05                                                  (±)-FISCH  2.07 ± 0.35                                                  (±)-Br-TISCH                                                                             2.84 ± 0.21                                                  Spiperone     488 ± 58                                                     Ketanserin    1881 ± 225                                                   Apomorphine   >2000                                                           Propanolol    >3000                                                           ______________________________________                                    

The compounds of this invention can exist as either R- or S- isomers. Itis important to note that the aforementioned data were obtained using aracemic mixture of FISCH. Optical resolution of the isomers hasindicated that the R+ isomer is the active isomer and that the S- isomeris inactive.

The above-described test results indicate that [¹²⁵ I]FISCH displays invivo and in vitro properties superior to those of [¹²⁵ I]IBZP andsuggest that the compound and the structurally related compoundsencompassed by Formula I, especially in the form of the resolved activeR-(+)-isomer, should when appropriately labeled be useful imaging agentsfor imaging D-1 receptors in the living human brain using well-knownmethods such as SPECT. By virtue of their D-1 receptor capability, thenovel compounds of Formula I may also possess as yet undefinedtherapeutic value.

Preferred compounds of this invention are those wherein, independentlyor in combination, (1) Y=H and X=Cl; (2) A=H; (3) Hal=I; (4) Hal=¹²³ I,¹²⁵ I or ¹³¹ I; and (5) Z=Hal. Specific examples of compoundscontemplated within the scope of this invention ar presented in Table 3.

                  TABLE 3                                                         ______________________________________                                         ##STR7##                                                                     X        Y        Z               A                                           ______________________________________                                        Cl       H        4'-Br           H                                           Cl       H        4'-Cl           H                                           OH       Cl       4'-I            H                                           Cl       H        4'-CHCHI        H                                           Cl       H        4'-CH.sub.2 I   H                                           Cl       H        4'-CH.sub.2 CH.sub.2 I                                                                        H                                           Cl       H        4'-CH.sub.2PhI  H                                           Cl       H        4'-CH.sub.2I    H                                           Cl       H        4'-(CH.sub.2).sub.2 CHCHI                                                                     H                                           Cl       H        3'-CHCHI        H                                           Cl       H        3'-CH.sub.2 I   H                                           Cl       H        3'-CH.sub.2 CH.sub.2 I                                                                        H                                           Cl       H        3'-CH.sub.2PhI  H                                           Cl       H        3'-CH.sub.2I    H                                           Cl       H        3'-(CH.sub.2).sub.2 CHCHI                                                                     H                                           Cl       H        3'-I            H                                           Cl       H        5'-I            H                                           Cl       H        2'-I            H                                           Cl       H        6'-I            H                                           Cl       H        4'-I            2'-CH.sub.3                                 Cl       H        4'-I            2'-CH.sub.3 Ph                              CH.sub.3 H        4'-Br           H                                           CH.sub.3 H        4'-Cl           H                                           CH.sub.3 Cl       4'-I            H                                           CH.sub.3 H        4'-CHCHI        H                                           CH.sub.3 H        4'-CH.sub.2 I   H                                           CH.sub.3 H        4'-CH.sub.2 CH.sub.2 I                                                                        H                                           CH.sub.3 H        4'-CH.sub.2PhI  H                                           CH.sub.3 H        4'-CH.sub.2I    H                                           CH.sub.3 H        4'-(CH.sub.2).sub.2 CHCHI                                                                     H                                           CH.sub.3 H        3'-CHCHI        H                                           CH.sub.3 H        3'-CH.sub.2 I   H                                           CH.sub.3 H        3'-CH.sub.2 CH.sub.2 I                                                                        H                                           CH.sub.3 H        3'-CH.sub.2PhI  H                                           CH.sub.3 H        3'-CH.sub.2I    H                                           CH.sub.3 H        3'-(CH.sub.2) .sub.2 CHCHI                                                                    H                                           CH.sub.3 H        3'-I            H                                           CH.sub.3 H        5'-I            H                                           CH.sub.3 H        2'-I            H                                           CH       H        6'-I            H                                           CH.sub.3 H        4'-I            2'-CH.sub.3                                 CH.sub.3 H        4'-I            2'-CH.sub.3 Ph                              ______________________________________                                    

The preparation and testing of the compounds of this invention arediscussed in more detail in the following examples which are notintended to limit the scope of this invention. In all examples, ProtonNMR was recorded on a Varian EM 360A spectrometer. The chemical shiftswere reported in ppm downfield from an internal tetramethylsalinestandard. Infrared spectra were obtained with a Mattson Polaris FT-IRspectrometer. Melting points were determined on a Meltemp apparatus arereported uncorrected. Elemental analyses were performed by AtlanticMicrolabs, Inc., of Norcross, Ga. and were within 0.4% of thetheoretical values.

EXAMPLE 1

3-Chloro-4-methoxyphenethyl amine (1). Methoxyphenethyl amine (39.4 g,0.261 mol) was dissolved in water (300 mL) and concentrated HCl(22mL).To this solution was added chlorine gas (20.3 g, 0.287 mol) in glacialacetic acid (300 mL) over a 15 minute period while maintaining thetemperature below 35° C. After standing for ten minutes, the volatileswere removed in vacuo and the dark solid residue was dissolved inabsolute ethanol (100 mL) and allowed to crystallize at -10° C. Thecollected precipitate was dissolved in a mixture of saturated sodiumbicarbonate (400 mL) and dichloromethane (400 mL). The organic layer wasseparated and dried over anhydrous sodium sulfate. It was condensed on arotorevaporator to afford a dark oil which was distilled (115°-116°C./1.75 mm Hg) to give 12.8 g(26.4%) of a clear oil. 1R (neat) 3600-3310(br,NH₂), 1600, 1500, 1250 and 1060 cm⁻¹ ; 1H NMR(CDCl₃)δ,d 7.36-6.71(m, 3H, ArH), 3.85 (S, 3H, OCH₃), 3.15-2.48 (m, 4H, (CH₂)₂), 1.12(S, 2H,NH₂).

EXAMPLE 2

N-[2-(4'-Bromophenyl)-2-hydroxyethyl]-3-chloro-4-methoxyphenethylamine(2). Compound 2 (6.40 g, 0.034 mol) and 4-bromostyrene oxide (6.90 g,0.034 mol) were dissolved in acetonitrile (50 mL) and refluxedovernight. The solvent was evaporated under reduced pressure and a gummyresidue was triturated with ether. The white powder was filtered toafford 6.5 g (40%): mp 83°-84° C., IR (KBr)λ3400 (br, NH), 3140 (br,OH), 1500, 1400, 1250, 1050 cm⁻¹ ; 1H NMR (CDCl₃)δ,d 7.60-6.70 (m, 7H,ArH), 4.80-4.48 (m, 1H, CH), 3.85 (S, 3H, OCH₃), 3.00-2.40 (m, 6H,(CH₂)₃), 2.55 (S, 1H, NH).

EXAMPLE 3

7-Chloro-8-methoxy-1-(4,-bromophenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine(3). The hydroxy amine, 3 (7.4 g, 0.019 mol), was added in portions toconcentrated sulfuric acid (60 mL) with stirring, keeping thetemperature below 12° C. The reaction mixture was then stirred at 8° C.for 30 min. and then at room temperature for 90 min. The mixture waspoured into ice (500 g); concentrated ammonium hydroxide (100 mL) wasadded followed by solid sodium hydroxide (40 g) while maintaining thetemperature below 30° C. The precipitate was extracted intodichloromethane and the organic layer was dried over anhydrous sodiumsulfate and evaporated under reduced pressure to afford 6.5 g (93%) of alight yellow solid, which was purified by column chromatography (silicagel, CH₂ Cl₂ :MeOH:NH₄ OH;95:5:l) to obtain 3, 5.9 g (84%): mp 139°-140°C. (lit 136°-37° C.);FT-IR(KBr)δ 3430 (br,NH), 1500, 1480, 1400, 1050cm⁻¹ ; ¹ H NMR (CDCl₃)δ,d 7.65-7.31 and 7.10-6.89 (AA'BB', 4H, ArH'),7.13 (S, 1H, ArH #6), 6.50 (S, 1H, ArH #9) 4.29-4.05 (m, 1H, CH), 3.72(S, 3H, OCH₃), 3.45-2.53 (m, 6H, (CH₂)₃), 1.92 (S, 1H, NH).

EXAMPLE 4

7-Chloro-8-methoxy-1-(4'-bromophenyl)-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine(4). To a solution of benzazepine 3 (7.20 g, 19.6 mmol) in formic acid(2.3 g) was added 37% benzaldehyde (1.8 g). The mixture was heated to90°-100° C. for four hours. After cooling the reaction mixture to roomtemperature, 4N hydrochloric acid solution (5.16 mL) was added. Themixture was condensed to dryness under reduced pressure. The residue wasdissolved in water and then made basic with 25% sodium hydroxidesolution. The mixture was extracted three times with dichloromethane.The combined organic layers were dried over anhydrous sodium sulfate.The solvent was evaporated to obtain a solid which was purified bycolumn chromatography (silica gel; CH₂ Cl₂ :MeOH:NH₄ OH;95:5:l) to give4, 6.0 g (80%) mp 116°-118° C.; FT-IR (KBr)λ1500, 1380, 1270 and 1060cm⁻¹ ; ¹ H NMR (CDCl₃)δ,d 7.65-7.35 and 7.21-6.90 (AA'BB',4H, ArH'),7.13 (S, 1H, ArH #6), 6.38 (S, 1H, ArH #9), 4.40-4.10 (m, 1H, CH), 3.70(S, 3H, OCH₃), 3.10-2.45 (m, 6H, (CH.sub. 2)₃), 2.37 (S, 3H, NCH₃).Anal. Calcd for C₁₈ H₁₉ BrCINO: C,H,N.

EXAMPLE 5

7-Chloro-8-methoxy-l-(4'-tri-n-butyltinphenyl)-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine(5). The n-methyl benzazepine 4 (2.0 g, 5.2 mmol) in dried THF (50 mL)was cooled to -78° C. in a dry ice-acetone bath. To this solution,n-butyllithium (4.0 mL, 6.4 mmol) was added with stirring. The reactionsolution turned dark red immediately. Tri-n-butyltin chloride (1.5 mL)was added to the reddish solution. After stirring at -78° C. for fiveminutes the reaction mixture was quenched with ammonium chloridesolution (3 mL, saturated). The mixture was allowed to warm to roomtemperature and THF was evaporated under reduced pressure. The residuewas extracted with dichloromethane. The organic layer was dried overanhydrous sodium sulfate. After evaporating the solvent, the desiredproduct, 5, was separated by column chromatography (silica gel; CH₂ Cl₂:MeOH:NH₄ OH;95:5:l) to obtain 1.8 g (58%): FT-IR (neat)λ, 2960-2800(strong and broad band of n-butyl group), 1600, 1500, 1405, 1270 and1100 cm⁻¹ ; ¹ H NMR (CDCl₃)δ, d 7.65-7.38 and 7.25-7.03 (AA'BB',4H,ArH'), 7.13 (S, 1H, ArH #6), 6.30 (S, 1H, ArH #9), 4.54-4.17 (m, 1H,CH), 3.60 (S, 3H, OCH₃), 3.10-2.59 (m, 6H, (CH₂)₃);2.40 (S, 3H, NCH₃),1.70-0.65 (m, 27H, Sn(C₄ H₉)₃). Anal. calcd. for C₃₀ H₄₆ CINOSn: C,H,N.

EXAMPLE 6

7-Chloro-8-methoxy-1-(4'-iodophenyl)-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine(6). A 0.1M solution of iodine in chloroform was added to a solution oftri-n-butyltin derivative of benzazepine 5 (500 mg, 0.85 mmol) inchloroform at room temperature until the color of iodine persisted. Themixture was stirred overnight at room temperature. Then a solution ofpotassium fluoride (1M, 1 mL, 1 mmol) in methanol and a 5% aqueoussodium bisulfite solution (1 mL) were added respectively. After fiveminutes of stirring, water (2 mL) was added. The organic layer wasseparated and the aqueous layer was extracted with chloroform twice. Thecombined organic layers were dried over anhydrous sodium sulfate. Thesolvent was evaporated under reduced pressure to obtain a yellow solidwhich was purified by column chromatography (silica gel; CH₂ Cl₂ :MeOH:NH₄ OH; 95:5:1) to yield the product, 6: 342 mg (94%):mp 130°-132° C;.FT-IR (KBr)λ1500, 1460, 1400, 1260 and 1110 cm⁻¹ ; ¹ H NMR (CDCl₃)δ,d7.85-7.48 and 7.10-6.75 (AA'BB', 4H, ArH'), 7.13 (S,1H, ArH #6), 6.35(S, 1H, ArH #9), 4.41-4.01 (m,1H, CH), 3.70 (S, 3H, OCH₃), 3.15-2.50 (m,6H, (CH₂)₃), 2.38 (S, 3H, NCH₃). Anal. calcd. for C₁₈ H₁₉ CIINO: C, H,N.

EXAMPLE 7

7-Chloro-8-hydroxy-1-(4,-iodophenyl)-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine(7). A solution of iodobenzazepine 6 (342 mg, 0.80 mmol), in drieddichloromethane, was cooled in a dry ice-isopropanol bath. To thisstirred solution was added BBr₃ solution (1.6 mL, 1.6 mmol), dropwise.The reaction mixture was then allowed to warm to room temperature. Thestirring was continued for two hours. The reaction mixture was partlyconcentrated and chilled in an ice bath. Methanol was added to themixture and it was stirred for several hours at room temperature. Afterthe methanol had been evaporated under reduced pressure, the residue wasstirred with water. The mixture was made strongly basic with 10% sodiumhydrozide. The precipitate was filtered. The pH of the filtrate wasadjusted to 7-8 with dilute hydrochloric acid. The cloudy mixture wasextracted several times with ethyl acetate. The combined organic layerswere dried over anhydrous sodium sulfate. The solvent was evaporatedunder reduced pressure to obtain 110 mg (33%): mp 216°-218° C.; FT-IR(KBr)λ3450 (br, OH), 1500, 1460, 1400, 1100, 1060 and 1000 cm⁻¹ ; ¹ HNMR (CDCl₃ +DMSO(d₆))δ,d 7.80-7.52 and 7.10-6.85 (AA'BB', 4H, ArH'),7.10 (S, 1H, ArH #6), 6.32 (S,1H, ArH,#9), 4.31-3.92 1H, (m, 1H, CH),3.10-2.65 (m, 6H, (CH₂)₃), 2.35 (S, 3H, NCH₃). Anal. calcd. for C₁₇ H₁₇CINO: C, H, N.

EXAMPLE 8 Radiolabeling

Aqueous hydrogen peroxide (10 uL, 30% w/v) was added to a mixture of 10μL of compound 5 (1 mg/mL), 100 μL of 50% EtOH/H₂ O, 10 μL IN HCl and 5μL of sodium [¹²⁵ ]iodide (2-3 mCi, carrier-free, Sp. Act. 2,200Ci/mmol) in a sealed vial. The reaction was allowed to proceed at 23° C.for 2 hr, after which it was terminated by the addition of 0.5 ml ofsodium bisulfite (100 mg/mL). The reaction mixture was made basic viathe addition of 100 mg NaHCO₃ and extracted with ethyl acetate (3×1 mL.The combined organic layers were passed through an anhydrous sodiumsulfate column (0.2 cm×5 cm), and evaporated to dryness by a stream ofnitrogen. The residue was dissolved in 100% ethanol (50-100 μL), and thedesired product, [¹²⁵ l]6, was isolated from the unreacted compound 5and a small amount of unknown radioactive impurities by HPLC using areverse phase column (PRP-1, Hamilton Inc.) and an isocriatic solvent of90% acetonitrile/10% pH 7.0 buffer (5 mM, 3,3-dimethyl glutaric acid).The appropriate fractions were collected, condensed, and re-extractedwith ethyl acetate (1×3 ml). The solution containing the no-carrieradded product was condensed to dryness and redissolved into 100% ethanol(purity 99%, overall yield 75%).

To an anhydrous CH₂ Cl₂ solution of [¹²⁵ l]6 under an argon atmospherewas added BBr₃ (40 μL, 1 M in CH₂ Cl₂). The reaction was terminatedafter 1 hr at 23° C. The mixture was condensed to dryness, and theresidue was dissolved into 100% EtOH (100 μL). The desired product, [¹²⁵l] FISCH, was again separated from a small amount of unknown radioactiveimpurities by the same HPLC system but using 80%/20%acetonitrile/buffer. The appropriate fractions were collected,condensed, and re-extracted with ethyl acetate (1×3 ml). The solutioncontaining the no-carrier added product was condensed to dryness andredissolved into 100% ethanol (purity 99%, overall yield 75%). Afterdilution with saline, this agent was used in the in vivo and in vitrostudies.

The following techniques were used in the in vivo and in vitro studiesreported herein.

Biodistribution in Rats

Biodistribution of [¹²⁵ l]FISCH was studied in male Sprague Dawley rats(225-300g) which were allowed free access to food and water. While underhalothane anesthesia, 0.2 ml of a saline solution containing [¹²⁵l]FISCH was injected directly into the femoral vein, and the rats weresacrificed at various time points post injection by cardiac excisionunder halothane anesthesia. The organs of interest were removed, weighedand radioactivity was counted using a Beckman gamma automatic counter(Model 4000). The percent dose per organ was calculated by a comparisonof the tissue counts to suitably diluted aliquots of the injectedmaterial. Total activities of blood and muscle were calculated assumingthat they are 7% and 40% of total body weight, respectively.

Regional brain distribution in rats was obtained after an iv injectionof [¹²⁵ l]FISCH. By dissecting, weighing and counting samples fromdifferent brain regions (cortex, striatum, hippocampus and cerebellum),% dose/gram of samples was calculated by comparing the sample countswith the counts of the diluted initial dose. The uptake ratio of eachregion was obtained by dividing % dose/gram of each region with that ofthe cerebellum.

Tissue Preparation

Male Sprague-Dawley rats (200-250g) were decapitated, and the brainswere removed and placed in ice. Striatal tissues were excised, pooledand homogenized in 100 volumes(w/v) of ice-cold Tris-HCl buffer (50 mM),pH 7.4. The homogenates were centrifuged at 20,000×g for 20 min. Theresultant pellets were rehomogenized in the same buffer and centrifugedagain. The final pellets were resuspended in assay buffer containing: 50mM Tris buffer pH 7.4, 120 mM NaCl, 5 mM KCl, 2mM CaCl₂ and 1 mM MgCl₂.

Binding Assays

The binding assays were performed by incubating 50 μl of tissuepreparations containing 40-60μg of protein with appropriate amounts of[¹²⁵ l]FISCH ligand and competitors in a total volume of 0.2 ml of theassay buffer. After an incubation period of 20 min at 37° C. (withstirring), the samples were rapidly filtered in the cell harvester(Brandel M-24R) under vacuum through Whatman GF/B glass fiber filterspretreated with 0.2% protamine sulfate and washed with 3×5ml of cold (4°C.) 50 mM Tris-HCl buffer, pH 7.4. The nonspecific binding was obtainedin the presence of 10 μM SCH-23390. The filters were counted in a gammacounter (Beckman 5500) at an efficiency of 70%.

Data Analysis

Both Scatchard and competition experiments were analyzed using theiterative non-linear least squares curve-fitting program LIGAND.

What is claimed is:
 1. A dopamine receptor agent comprising a compoundof the formula ##STR8## where X is selected from the group consisting ofOH, Cl and CH₃ ;Y is selected from the group consisting of H, Cl andCH₃, provided that, when X is Cl, then Y is either H or CH₃, and when Yis H or CH₃, then X is Cl; Z is selected from the group consisting ofHal; C═CH--Hal, alkylene--Hal; and C₁ -C₁₀ alkylene--C═CH═Hal; C₁ -C₁₀alkylene-phenyl-Hal; Hal is a radioactive halogen isotope; and A isselected from the group consisting of H, C₁ -C₅ alkyl, and C₁ -C₅alkylene-phenyl.
 2. A method of imaging dopamine D-1 receptors in apatient comprising administering to said patient an effective quantityof the dopamine receptor imaging agent of claim 1 and measuring thegamma ray or photon emissions therefrom.